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US6284277B1 - Stable freeze-dried pharmaceutical formulation - Google Patents

Stable freeze-dried pharmaceutical formulation Download PDF

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US6284277B1
US6284277B1 US09/066,387 US6638798A US6284277B1 US 6284277 B1 US6284277 B1 US 6284277B1 US 6638798 A US6638798 A US 6638798A US 6284277 B1 US6284277 B1 US 6284277B1
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freeze
mannitol
active ingredient
alanine
concentration
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Colette Bouloumie
Thierry Breul
Laurence Colliere
Philippe Faure
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Sanofi SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the present invention relates to a pharmaceutical formulation provided in the form of a freeze-dried product and containing at least one active ingredient of nonprotein nature. More particularly, the invention relates to such a formulation, stable at temperatures which may be as high as 25° C. to 40° C., which may be either reconstituted in liquid form by addition of a solvent for its administration via the parenteral or oral route, or directly administered via the oral route, to man or to animals.
  • the active ingredient contained in the formulation according to the invention may be alone or else combined with another active ingredient of protein or nonprotein nature.
  • freeze-drying may have a considerable effect on the degradation of the pharmaceutical active ingredients in a formulation, as well as a strong impact on their stability in freeze-dried form.
  • the various variables which affect these parameters are mainly the pH, the quantity of salts present, the type and quantity of excipients in the formulation, the type of cryoprotection chosen, as well as the temperatures, pressure and time chosen for the freezing, sublimation and drying operations. These different variables influence the physical state of the freeze-dried product obtained, namely: vitreous amorphous, soft amorphous, crystalline or a combination of these states.
  • amino acids preferably glycine
  • polyols preferably mannitol
  • the literature teaches that the presence of an amino acid, of a polyol, for example mannitol, of a crystalline phase or of an amorphous phase may have, besides certain advantages, disadvantages which lead, in the case of freeze-dried products containing particularly sensitive active ingredients, to relatively short shelf lives and/or storage temperatures for these freeze-dried products which are less than 8° C. It would, however, be particularly advantageous, especially for an ambulatory treatment, to be able to obtain a formulation which is stable at room temperature until it is reconstituted and to thereby avoid its storage in a refrigerator before or during treatment.
  • Alanine in crystallized form, has the advantage of preventing the collapse of the freeze-dried product during sublimation and drying and or allowing the production of a freeze-dried product with a greater specific surface area and therefore allows a more rapid drying (Pikal M. J., Freeze-drying of proteins, Biopharm., 26-30 October 1990).
  • mannitol in the composition of a freeze-dried product is generally justified as freeze-drying ballast, that is to say that it makes it possible both to maintain the solid and rigid structure of the volume of the freeze-dried product corresponding to the volume of solution to be freeze-dried, but its presence also makes it possible to adjust the isotonicity of the reconstituted solution to be injected.
  • mannitol is the predominant excipient in the composition of a freeze-dried product, it is most often in crystalline form (Lyophilized formulations recombinant tumor necrosis factor, Hora M. S., Rana R. K., Smith F. W., Pharm. Res., 1992, 9 (1), 33-36).
  • the crystallized substances have less rapid dissolution rates than the amorphous substances. Indeed, more energy is required to detach a molecule from an organized lattice of a crystalline arrangement than to detach it from a disorganized assembly of an amorphous state. Sometimes, the dissolution rate becomes insufficient to allow a sufficiently rapid absorption of these substances, which may lead to a decrease in their activity, especially in the case of molecules which are not very stable in solution.
  • the perfect regularity of crystals being an ideal case, the heterogeneity of the crystalline phase and the polymorphism which are obtained for the same substance and between associated substances induce different rates of dissolution for the same substance and between each of the substances, which may result in unreproducible therapeutic effects (Galénica 2, Biopharmacie 2nd edition, 1982, technique and documentation).
  • the amorphous form dissolves more rapidly than the crystallized form and does not exhibit the disadvantages linked to the heterogeneity and to the polymorphism of the crystallized substances.
  • the presence of additives in the amorphous state stabilizes the activity of certain enzymes proportionally to the concentration of the additive according to Izutsu K. L., Yoshioka S., Terao T., Decreased protein-stabilizing effects of cryoprotectants due to crystallization, Pharm. Research., 1993, 10, No. 8, 1232-1237.
  • cryoprotective effect of the excipients is attributed to the amorphous state of the glycine in the freeze-dried product obtained (Pikal M. J., Dellermann K. M., Roy M. L. Riggin M. N., The effects of formulation variables on the stability of freeze-dried Human Growth Hormone, Pharm. Research., 1991, 8, No. 4, 427-436).
  • the discovery of a surprising synergistic effect resulting from the coexistence of an amorphous phase and a crystalline phase which has the consequence of stabilizing the freeze-dried pharmaceutical active ingredient forms the basis of the present invention.
  • the present invention therefore describes the production of this effect for specific mannitol/alanine ratios.
  • the present invention relates to a freeze-dried pharmaceutical formulation consisting of an amorphous phase and a crystalline phase, comprising an effective quantity of at least one nonprotein pharmaceutical active ingredient, mannitol and alanine, the latter two excipients being in a mass ratio R of between 0.1 and 1, R being the ratio of the mass of the mannitol to the mass of the alanine.
  • the active ingredient included in the said formulation remains stable at temperatures which may range from 25° C. to 40° C. in freeze-dried form. Where appropriate, the dissolution of the freeze-dried product obtained is rapid and complete.
  • the freeze-dried product does not have a collapsed appearance and its water content is compatible with maintaining the stability of the active ingredient.
  • freeze-dried product consists of an amorphous phase and a crystalline phase
  • the amorphous phase predominantly consists of mannitol and active ingredient
  • the crystalline phase predominantly consists of alanine
  • the amorphous phase demonstrated by differential scanning calorimetry, cryoprotects the pharmaceutical active ingredient during freezing, the active ingredient itself being dispersed in this amorphous form, and the crystalline phase, demonstrated by X-ray diffractometry, fixes the structure of the freeze-dried product and avoids its collapse.
  • the subject of the present invention is the production of stable freeze-dried products containing a pharmaceutical active ingredient cryoprotected by an amorphous solid phase consisting completely or partially of mannitol, this amorphous phase coexisting within the freeze-dried product obtained after sublimation and drying of the frozen solution, with a crystalline phase consisting essentially of alanine.
  • the subject of the present invention is also a process for the preparation of freeze-dried pharmaceutical formulations comprising at least one nonprotein active ingredient characterized in that a mixture of the said active ingredient, mannitol and alanine in which the mannitol and alanine are present in the ratio of between 0.1 and 1, R being the ratio of the mannitol mass to the alanine mass,is freeze-dried.
  • excipients normally used in freeze-dried forms may be introduced into the formulation according to the present invention, such as for example buffers or acid-bases which make it possible to adjust the pH, surfactants, salts, preservatives, especially antibacterial preservatives, antioxidants or chelating agents, excluding excipients which, in the freeze-dried product containing the active ingredient, would prevent the coexistence of the crystalline phase consisting predominantly of mannitol and of the crystalline phase consisting predominantly of alanine, such as for example certain protein derivatives of animal or plant origin such as gelatines, dextrins or proteins extracted from wheat grain or soya bean, gums such as agar or xanthan, polysaccharides, alginates, carboxymethylcelluloses, pectins, synthetic polymers such as polyvinylpyrrolidone or complexes of a polysaccharide nature such as acacia gelatine.
  • buffers or acid-bases which make it possible to adjust the pH, sur
  • buffers which may be introduced into the formulation according to the present invention, there may be mentioned in particular carbonate, borate, phosphate, citrate, tri(hydroxy-methyl)aminomethane, maleate and tartrate buffers, it being understood that the acids and bases composing said buffers may also be introduced alone.
  • surfactants which may be introduced into the formulation according to the present invention, there may be mentioned in particular polysorbates, poloxamers, tyloxapol, lecithins.
  • the salts which may be introduced into the formulation according to the present invention, there may be mentioned in particular the sodium salts such as ededate (tetrasodium EDTA), chloride, docusate (sodium 1,4-bis(2-ethylhexyl)sulphosuccinate), bicarbonate, glutamate; potassium acetate; dipotassium carbonate and magnesium stearate.
  • ededate tetrasodium EDTA
  • docusate sodium 1,4-bis(2-ethylhexyl)sulphosuccinate
  • bicarbonate glutamate
  • potassium acetate potassium acetate
  • dipotassium carbonate magnesium stearate
  • preservatives which may be introduced into the formulation according to the present invention, there may be mentioned in particular methyl and propyl para-hydroxybenzoate, benzethonium chloride, sodium mercurothiolate, phenylmercuric nitrate, benzyl alcohol, phenol and metacresol.
  • the coexistence of the amorphous mannitol phase and the crystalline alanine phase is independent of the presence and of the concentration of the buffer used to adjust the pH of the solution, but it depends on the ratio R defined above.
  • formulation of the solutions to be freeze-dried leading to the formulations of the invention are the following:
  • One or a combination of pharmaceutical active ingredients, a pharmaceutically acceptable buffer for adjusting the pH, mannitol and alanine with a mass ratio R mass of mannitol/mass of alanine of between 0.1 and 1, water for injectable preparations, as well as, if necessary, antibacterial preservatives and excipients which allow solubilization of the active ingredient or ingredients.
  • the alanine/mannitol mixture is predominant.
  • the quantity of active ingredient present is limited by its solubility in water.
  • the formulations of the invention indeed result from the freeze-drying of aqueous solutions in which the active ingredient is perfectly dissolved.
  • any excipient is present in the formulation in a quantity below the quantity of the alanine/mannitol mixture.
  • the solutions to be freeze-dried are prepared in the following manner:
  • the desired quantities of buffer, alanine, mannitol, preservatives and active ingredient are added, at the appropriate dissolution temperature, to the quantity of water for injectable preparations or of solubilizing agent necessary for their solubilization until complete dissolution is obtained.
  • the solutions obtained are filtered in a sterile medium and distributed into containers, preferably vials or capsules.
  • freeze-drying of the solutions is carried out as follows:
  • the solution follows a cycle comprising freezing, then sublimation and drying adapted to the volume to be freeze-dried and to the container containing the solution.
  • a freezing rate close to ⁇ 2° C./min is chosen in an Usifroid (France) freeze-drier type SMH15, SMJ100 or SMH2000.
  • the sublimation and drying times, temperatures and pressures are adjusted according to the volumes of solution to be freeze-dried and the residual water content desired in the freeze-dried product.
  • a freeze-dried product is then obtained in which the alanine exists in crystallized form, and the mannitol in a completely or partially amorphous form.
  • the freeze-dried product may be stored at 25° C. and even up to 40° C. without adversely affecting the chemical and biological stability of the active ingredient which it contains.
  • the active ingredient or the combined active ingredients, of the nonprotein type, formulated according to the present invention may be analgesics, anti-inflammatory agents, antispasmodic agents, anticancer agents or active ingredients which can be used in cardiology, angiology, gastro-enterology, haematology and haemostasis, hepatology, infectiology, neurology-psychiatry, rhinology, rheumatology, toxicology, urology, or in the diagnostic field or as metabolism and nutrition regulators.
  • any product can constitute the active ingredient of the formulations of the present invention which represent a considerable technical advance in the pharmaceutical technique.
  • the active ingredients which are most adapted to the formulations of the present invention are those whose stability in aqueous solution is problematical. It is however conceivable to apply the present invention to active ingredients which have no specific problem of stability.
  • the active ingredient of the freeze-dried pharmaceutical formulations of the present invention may be chosen especially from the group consisting of:
  • phenylalkanoic acids for example ketoprofen
  • nonsteroid anti-inflammatory agents of the “oxicam” type for example piroxicam, isoxicam, tenoxicam;
  • corticosteroids for example methylprednisolone
  • bile acids for example ursodeoxycholic acid or one of its pharmaceutically acceptable salts with inorganic or organic bases, preferably its sodium salt;
  • anthracyclines for example doxorubicin, epirubicin, idarubicin, daunorubicin, pirarubicin;
  • platinum derivatives for example cisplatin, oxaliplatin, carboplatin;
  • derivatives of alkaloids from Vinca minor for example vinblastine, vincristine;
  • derivatives of alkaloids from rye ergot for example dihydroergotamine, dihydroergotoxine, nicergoline;
  • derivatives of purine or pyrimidine bases for example acyclovir, gancyclovir, cytarabine;
  • prostaglandins for example sulprostone, alprostadil;
  • benzodiazepines for example dipotassium clorazepate, devazepide;
  • beta-lactam antibiotics for example piperacillin, tazobactam;
  • macrolide antibiotics for example erythromycin or one of its derivatives, in general a leukomycin;
  • antibiotics of the tetracycline family for example minocycline
  • antibiotics of the chloramphenicol type for example thiamphenicol
  • nitrogenous mustards for example chlorambucin and nitrosoureas, for example carmustine and streptozocin.
  • the nitrogenous mustards and the nitrosoureas are described in greater detail in Pharmacologie by M. Schorderet et al., 1992, 2nd edition, chapter 69, Ed., Frison, Roche, Paris;
  • H 2 antagonists for example ranitidine, famotidine or one of their pharmaceutically acceptable salts
  • vitamins for example thiamine, riboflavin, nicotinamide, pyridoxine, sodium panthotenate, biotin, ascorbic acid, folic acid, cyanocobalamin, retinol, cholecalciferol, alphatocopherol, cobalamide, hydroxycobalamide;
  • antitumour agents chosen from taxol, taxotere and their analogues, dacarbazine, methotrexate, plicamycin, thiotepa, streptozocin;
  • cardiovascular medicines chosen from molsidomine or one of its pharmaceutically acceptable salts, especially its hydrochloride, linsidomine, acetazolamide, meclofenoxate, diltiazem, sodium nitroprussiate;
  • haematological medicines chosen from ticlopidine or one of its pharmaceutically acceptable salts, especially its hydrochloride, molgramostim, folinic acid;
  • anticoagulant and antithrombotic medicines chosen from heparin, low-molecular weight heparin in the form of nadroparin calcium, parnaparin sodium, dalteparin sodium, enoxaparin sodium, ardeparin sodium, certoparin sodium, reviparin sodium, minolteparin sodium, natural or synthetic antithrombotic pentasaccharides;
  • heparinoids for example lomoparan
  • plant extracts for example based on willow, harpagophytum, ginseng, fucus;
  • a gene a DNA or RNA fragment intended for gene therapy, an oligonucleotide, an antisense oligonucleotide, nucleotides associated with protein compounds such as for example extracts of ribosome fractions, attenuated or inactivated live viruses;
  • sodium pamidronate, sodium alandronate, sodium risendronate and other diphosphonates active as antiosteoporotic agent especially ⁇ [(4-chlorophenyl)thio]methylene ⁇ bis(phosphonate) tiludronate or disodium salt (SR 41319) in hemihydrate or monohydrate form;
  • 5-HT 2 antagonists especially ketanserine, ritanserine, (1Z,2E))-1-(2-fluorophenyl)-3-(4-hydroxyphenyl)-prop-2-en-1-one-O-(2-dimethylaminoethyl)oxime (SR 46349) or one of its pharmaceutically acceptable salts;
  • angiotensin II especially tasosartan, telmisartan, losartan potassium, losartan combined with hydrochlorothiazide (HCTZ), eprosartan, candesartan cilexetil, valsartan, irbesartan or 2-n-butyl-3- ⁇ [2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl ⁇ -1,3-diazaspiro[4.4]non-1-en-4-one (SR 47436) and its pharmaceutically acceptable salts;
  • HCTZ hydrochlorothiazide
  • the active ingredient is chosen from 2- ⁇ [4-(2-enlorophenyl)thiazol-2-yl]aminocarbonyl ⁇ -indole-1-acetic acid or its potassium salt, irbesartan, clopidogrel, ursodeoxycholic acid and its sodium salt, 1-(2-naphthalen-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, N,N-dimethyl-N′-(pyridin-3-yl)methyl-N′-[4-(2,4,6-triisopropylphenyl)thiazol-2-yl]ethane-1,2-diamine fumarate, 2-[(5-(2,6-dimethoxyphenyl)-1- ⁇ 4-[(3-dimethylaminopropyl)methylcarbamoyl]-2-isopropylphenyl
  • a pharmaceutically acceptable salt of any one of the salifiable active ingredients listed above may also be selected as active ingredient.
  • the pharmaceutical active ingredient is preferably chosen from the group consisting of the potassium salt of the acid SR 27897 designated below as SR 27897B, irbesartan or SR 47436, clopidogrel, ursodeoxycholic acid or its sodium salt, SR 57746A and SR 27417A.
  • NTU nephelometric turbidity units
  • the organoleptic criteria for the freeze-dried products will be examined visually and will take into account the colour of the freeze-dried product, its structure (collapsed or otherwise), as well as the observation of a possible phase shift between the crust and the crumb of the freeze-dried product.
  • the water content of the freeze-dried products will be determined by coulometry according to the method described in Ph. Fr. Xth Ed. V. 3.5.6. A., by injecting 2 ml of methanol into the vial of freeze-dried product with the aid of a syringe. The water content will be expressed in percentage by weight of the freeze-dried product.
  • X-ray diffractometric analysis on the freeze-dried products will be carried out on a SIEMENS D500 TT diffractometer; source: CuKal; generator: 40 KV, 25 mA; back monochromator; slits: 1/1/1/0.16/0.6; sampling on a pyrex support; scanning range: 40 to 400 per minute for Bragg 2 theta.
  • DSC Differential scanning calorimetry
  • the SR 27897B assay will be carried out by liquid chromatography (Ph. Eur. 2 (1) V. 6.20.4. ) at 254 nm using a C18 graft column 25 cm long, 4.6 mm internal diameter and particle size 10 ⁇ m (Bischoff reference 25461840).
  • the mobile phase will consist of a volume for volume mixture of acetate buffer pH 4.0 (glacial acetic acid and concentrated ammonium hydroxide Merck) and of acetonitrile for chromatography (Sharlau reference Ac33).
  • the control solution will consist of a solution of SR 27897B (provided by Sanofibericht) at 50 ⁇ g per ml of methanol (Merck reference 6009).
  • the solution to be analyzed will be obtained by dissolving the freeze-dried product in 100 ml of ultrapurified water (Millipore, “Milli-Q” water). The flow rate will be 2 ml/min. The specific peak surface area obtained after injection of 20 ⁇ l of control solution and then of solution to be analyzed will be calculated for each of the chromatograms. The SR 27897B content of the freeze-dried product, expressed in mg/vial, will be determined from the calculation of these two surface areas.
  • the assay of the related substances (impurities) of SR 27897B in the freeze-dried product during preservation, a parameter indicative of the stability of the product, will also be carried out by liquid chromatography on a C18 graft column (Bischoff reference 25461840).
  • the mobile phase will consist of a gradient of acetonitrile and acetate buffer pH 4.0 whose composition is indicated in TABLE A:
  • the control solution will consist of a solution of SR 27897B (SanofiInstitut) at 10 ⁇ g per ml of methanol.
  • the solution to be analyzed will be obtained by dissolving the contents of a freeze-dried vial in 5 ml of methanol.
  • the flow rate will be 2 ml/min.
  • the specific peak surface area of the unknown impurities obtained on the chromatograms after injection of 20 ⁇ l of the solution to be analyzed, expressed in terms of the specific peak surface area of SR 27897B obtained after injection of 20 ⁇ l of the control solution, will be calculated in the same manner.
  • the content of each of the unknown impurities and the overall content of impurities of the freeze-dried SR 27897B expressed in percentage by weight of the product, can be determined from these calculations.
  • the SR 47436 assay will be carried out by HPLC liquid chromatography (Ph. Eur. 2 (1) V 6.20.4.) at 220 nm using a C18 graft silica column made of stainless steel, 25 cm long, 8 mm external diameter and 4 mm internal diameter, spherical silica of diameter 7 ⁇ m and of 120 ⁇ pore diameter having undergone an “end capping” treatment (reference column 720042 supplied by Chromoptic).
  • the mobile phase will consist of a mixture of 60 volumes of phosphate buffer solution pH 3.0 (phosphoric acid Prolabo reference 20624295, triethylamine Fluka reference 90340) and of 40 volumes of acetonitrile for chromatography (Merck reference 14291) with a flow rate of 1 ml/min.
  • the first control solution will consist of a solution of SR 47436 (Sanofilich) at 0.5 mg per ml of mobile phase.
  • the second control solution will consist of a solution containing 0.5 mg of SR 47436 and 0.5 mg of impurity corresponding to the opening product (Sanofibericht) per ml of mobile phase.
  • the solution to be analyzed will be obtained by dissolving the freeze-dried product in 10 ml of mobile phase.
  • the operating conditions will be checked by successive injection of the first and second control solutions that the operating conditions are satisfactory (resolution factor greater than 2 between the two peaks for an injection of 10 ⁇ l of the second control solution, coefficient of variation of the surface area of the peak less than or equal to 1% for a series of 5 injections of 10 ⁇ l of the first control solution).
  • the SR 47436 content in mg per freeze-dried product will be determined by calculating the specific peak surface areas obtained on the chromatograms.
  • the assay of the related substances (impurities) of SR 47436 will be carried out by HPLC liquid chromatography (Ph. Eur. 2 (1) V 6.20.4.) at 220 nm using a C18 graft silica column (cf. assay of SR 47436).
  • the mobile phase will consist of a mixture of 60 volumes of phosphate buffer pH 3.1 and 40 volumes of acetonitrile for chromatography with a flow rate of 1 ml/min.
  • the two control solutions will consist, for the first, of a solution of SR 47436 (Sanofibericht) at 0.5 mg per ml of methanol (supplied by SDS under the reference 0930221) and for the second, of a solution of SR 47436 at 0.5 ⁇ g per ml of methanol.
  • the solution to be analyzed will be obtained by dissolving the freeze-dried product in 10 ml of water for injectable preparations (IP). The analysis should be carried out within half an hour at the latest after the reconstitution.
  • the SR 57746A assay (Sanofilich) will be carried out by liquid chromatography at 224 nm using a C18 graft silica column 25 cm long, 4 mm internal diameter and particle size 7 ⁇ m (Macherey Nagel, reference 720042).
  • the mobile phase will consist of a mixture of 45 volumes of acetonitrile for chromatography (Rathburn reference RH 1016) and 55 volumes of buffer solution pH 3.0 (prepared by diluting 5.5 ml of phosphoric acid in 950 ml of filtered demineralized water (Millipore Alpha-Q), then by adjusting the pH to 3.0 with a triethylamine solution (Fluka, reference 90340) then by adding 10 ml of acetonitrile and by filling to 1000 ml with filtered demineralized water).
  • the control solution will consist of an SR 57746A solution at 15.0 mg per 100 ml of methanol (Carlo Erba, reference 414814).
  • the solution to be analyzed will be obtained by dissolving the freeze-dried product in 3.0 ml of a mixture consisting of 25 volumes of methanol and 75 volumes of filtered demineralized water.
  • the flow rate will be 1 ml per minute.
  • the specific peak surface area obtained after injection of 10 ⁇ l of control solution and then of solution to be analyzed will be measured for each of the chromatograms.
  • the SR 57746A content of the freeze-dried product, expressed in mg/vial, can be determined from the measurement of the two surface areas.
  • the assay of the related substances (impurities) of SR 57746A in the freeze-dried product during preservation will be also carried out by liquid column chromatography with the chromatographic conditions described in “Assays” in (Ph. Eur. 2 (1) V.6.20.4. ).
  • the control solution will consist of a solution of SR 57746A at 0.15 ⁇ g per ml of methanol.
  • the solution to be analyzed will be obtained by dissolving the contents of the freeze-dried product in 3 ml of a mixture of 25 volumes of methanol and of 75 volumes of filtered demineralized water. The flow rate will be 1 ml per minute.
  • the specific peak surface area of the unknown impurities obtained on the chromatograms after injection of 10 ⁇ l of the solution to be analyzed, expressed in terms of the specific peak surface area of SR 57746A obtained after injection of 10 ⁇ l of control solution will be measured in the same way.
  • the content of each of the unknown impurities and the overall content of impurities of the freeze-dried SR 57746A, expressed as percentage in terms of surface area, can be determined from these measurements.
  • TABLE 4 represents the results of the initial controls carried out on the freeze-dried products of SR 27897B for the water content (in % by weight of the freeze-dried product), the glass transition temperature Tg (in ° C. ) determined by DSC, and on the freeze-dried products taken up in water for IP for the turbidity (in NTU) and the pH.
  • TABLE 7 represents the total content of related substances (impurities) found in the freeze-dried products of SR 27897B after 6 months of storage at 5° C. and 40° C., shows that the stability is also excellent after this period of storage.
  • the diffractograms 3 and 4 of FIG. 1 represent the controls alanine and mannitol.
  • the line situated between 10° and 11°, characteristic of crystallized mannitol is not obtained for the two freeze-dried products of SR 27897B.
  • FIG. 2 represents the influence of the alanine to mannitol mass ratio on the glass transition temperature of the freeze-dried products. This figure shows us that the maximum glass transition temperature is obtained for (1/R)>1, that is to say for R of between 0 and 1. In general, the glass transition temperature is representative of the maximum temperature for stability of the freeze-dried product. Thus, the maximum temperature for stability of the freeze-dried product is reached for R of between 0 and 1.
  • TABLE 8 represents the results of the initial controls carried out on the freeze-dried products of SR 47436 for the water content, the total content of related substances (impurities) and on the freeze-dried products taken up in water for IP, for the pH.
  • TABLE 10 represents the total contents of related substances expressed as percentage of impurities, of the freeze-dried products of SR 47436 batch 13 after 3 months, 6 months and 9 months of storage at 5° C., 25° C. and 35° C.
  • TABLE 11 represents the total contents of related substances expressed as percentage of impurities, of the freeze-dried products of SR 57746A after 1 month and 3 months of storage at 5° C., 25° C. and 40° C. and of a freeze-dried product of SR 57746A reconstituted immediately (reference).
  • CONSTITUENTS Unit formula in (mg) SR 47436 5.0 mg Apyrogenic alanine 115.0 mg Apyrogenic mannitol 50.0 mg Potassium hydroxide 0.687 mg
  • composition of a freeze-dried product of SR 57746A (hydrochloride) to be taken up in 4 ml of water for IP.
  • composition of a solution of SR 57746A (hydrochloride) to be freeze-dried expressed in concentration for final volumes of solution which may be as high as 100 ml by addition of a sufficient quantity of water for IP.
  • composition of a freeze-dried product of SR 57746A (hydrochloride) to be taken up in 4 ml of water for IP.
  • composition of a solution of SR 57746A (hydrochloride) to be freeze-dried expressed in concentration for final volumes of solution which may be as high as 100 ml by addition of a sufficient quantity of water for IP.
  • CONSTITUENTS Unit formula in (mg) Apyrogenic alanine 18.0 mg Apyrogenic mannitol 9.0 mg Apyrogenic anhydrous citric acid 7.7 mg Polysorbate 80 1.0 mg White glass vial type 1 of 3 ml 1 Grey chlorobutyl pillar stopper 1 Blue flip-off aluminium capsule 1 diameter 13 mm

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ZA969176B (en) 1998-04-30
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IS4729A (is) 1998-04-29
ES2180805T3 (es) 2003-02-16
IL124214A (en) 2001-01-28
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AU713383B2 (en) 1999-12-02

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